Understanding and Targeting Common Mechanisms of Myotonic Dystrophy Types 1 and 2 Using Novel Repeat Expansion Mouse Models
Abstract
This proposal responds to the Fiscal Year 2022 Peer Reviewed Medical Research Program Neuroscience Portfolio in the Myotonic Dystrophy Topic Area and aligns with designated Foundational Studies and Treatment Strategic Goals. A large family of 50+ human diseases are caused by the expansion of small segments of DNA, termed repeats within specific genes. One of these diseases, myotonic dystrophy (DM), is the leading cause of adult-onset muscular dystrophy and develops as a type 1 (DM1) or type 2 (DM2) form. While both DM1 and DM2 have devastating effects on the heart and skeletal muscles, the central nervous system (CNS) is also severely affected resulting in excessive daytime sleepiness, and problems with attention, memory, and planning skills, as well as changes to the brain. How the disease develops at a cellular level is shared by both DM1 and DM2 as the repeat expansions: (1) attract and quarantine proteins that normally help the cell convert DNA and then RNA into proteins affecting a host of downstream process; (2) also get converted into toxic repeat proteins that clump together in cells. One central and remaining question in the field is how the processes that govern the quarantined proteins and toxic repeat proteins work and if these processes can be targeted to provide a disease therapy. Normally, researchers would use animal models to address these critical questions but current mouse models of DM1 do not mimic what happens in patients and there are no mouse models at all for DM2. In this proposal we will generate DM1 and DM2 mouse models to better understand the disease process and use these models to test how these two central disease processes are triggered in the CNS and if they can be corrected. At the completion of the project we expect to show that the mouse models mirror what happens in DM1 and DM2 patients and to better understand how these two disease processes interact with each other to cause this complex disease. In the short term, this proposal will make several new important mouse models that can be used to better understand the disease and identify ways to correct the underlying problems associated with DM. In the long term, the lessons learned from this research are likely to provide important clues to the disease process for the entire family of repeat expansions diseases, which also includes amyotrophic lateral sclerosis (ALS), Huntington s disease, and a large number of spinocerebellar ataxias.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310936
Entities
People
- Maurice Swanson
Organizations
- United States Army
- University of Florida